She was a daughter of Francesco II of Lesbos (a maternal grandson of Andronikos III Palaiologos) and Valentina Doria.
His grandfather died the following year, and was succeeded by Manuel II Palaiologos, a paternal uncle of John VII.
From 1399 to 1402, Manuel II embarked on a journey of Western Europe, seeking allies to use against Bayezid who was besieging Constantinople.
Bayezid lifted the siege in 1402 when Timur, founder of the Timurid dynasty, invaded Anatolia and the Ottoman Empire had to defend itself.
John VII remained in control of Constantinople until the return of Manuel II, whereupon Irene's husband was expelled from the city in 1403, under suspicion of conspiring to regain the throne.